A long-term goal in clinical immunology has been the development of vaccines that produce robust mucosal protection. It may be possible to create a new vaccine technology that is superior to existing methods by delivering DNA vaccines to the salivary gland. The proposed research will characterize the immune response to the HIV-1 gp120. Specifically, the proposal addresses the following aims: 1) Demonstrate that salivary gland DNA vaccination results in humoral mucosal immune responses that are superior to other vaccination methods; 2) Evaluate the utility of benign adjuvants to enhance salivary gland vaccination; 3) Determine the extent to which systemic T cell-mediated activity is stimulated 4) Establish protection against mucosal and systemic infection in a challenge model. The critical criteria that will demonstrate the utility of salivary gland DNA vaccination include either a strong mucosal immune response or enhanced T cell mediated response, combined with successful protection in challenge studies. If successful, this demonstration of feasibility will serve as the foundation for additional development towards clinical testing. Understanding more fully the potential of salivary gland vaccination is the first step to evaluating how this technology may compete with existing vaccine technologies, and will likely reveal additional clinical targets.